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Downmodulating Monocyte Activation for HIV-1 Associated Neurocognitive Disorders (HAND)

This study is not yet open for participant recruitment.
Verified May 2012 by University of Pennsylvania
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania
ClinicalTrials.gov Identifier:
NCT01600170
First received: May 14, 2012
Last updated: May 25, 2012
Last verified: May 2012
History of Changes
  Purpose

HIV associated neurological disorders (HAND), are a major problem even in ART treated people. HAND results from chronic inflammation which is largely attributed to expansion and activation of monocytes. These activated monocytes, some of which also carry virus to the brain, invade the CNS and release cytokines / chemokines resulting in further recruitment of monocytes, as well as release viral proteins which injure neurons and cause activation of other brain cells. Persistent monocyte/macrophage activation is thus a potential critical target for adjunctive therapy to treat or prevent HAND. The investigators therefore propose to study the effects of a statin drug (Atorvastatin), which has anti-inflammatory functions, on the monocyte activation status in vitro and in ART treated HIV+ individuals.

The investigators objectives are based on the hypothesis that Atorvastatin treatment will reduce the inflammatory and activated phenotype and function of monocytes which have been linked to HIV associated neuropathogenesis and occur in HIV infected subjects despite ART. In this study the investigators propose to

  1. determine how Atorvastatin modulates monocyte activation, intracellular signaling pathways and functions implicated in the pathogenesis of HAND in vitro
  2. define the effect of Atorvastatin on monocyte activation in HIV infected / ART treated subjects in a double blind, placebo controlled crossover study
  3. define gene expression patters of monocyte activation before and following statin treatment
  4. assess Atorvastatin effects on CNS immune activation markers and neurocognitive function in ART treated subjects.

Condition Intervention Phase
HIV Dementia
 Drug: Atorvastatin (generic Lipitor)
Drug: placebo
 Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by University of Pennsylvania:

Primary Outcome Measures:
  • Effects of Atorvastatin on peripheral blood monocytes [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    1. Peripheral blood monocyte surface markers CD16; CD14; CD163; CCR2;
    2. Plasma levels of monocyte associated inflammatory cytokines and chemokines: MCP-1; sCD14 and neopterin
    3. Monocyte gene expression patterns in ART treated HIV+ subjects.
    4. Monocyte / macrophage signaling pathways


Secondary Outcome Measures:
  • Effects of Atorvastatin on T cell and CSF activation markers [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    1. Immune activation markers in the CSF: MCP-1 and neopterin
    2. T cell activation markers: CD38 and CD25.
    3. Neurocognitive outcomes.


Estimated Enrollment: 30
Study Start Date: June 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Atorvastatin Drug: Atorvastatin (generic Lipitor)
Atorvastatin is an FDA approved prescription drug which is frequently used to lower cholesterol levels.It is available in the form of tablets ranging in dose from 10-80mg.
Placebo Comparator: Placebo Drug: placebo
A substance containing no medication and prescribed or given to reinforce a patient's expectation to get well.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Chronic HIV-1 infected individuals on HAART (with no change in treatment within 4 weeks of study entry) and willing to continue therapy for the duration of the study.
  2. HIV viral load less than 200 copies/ml for more than 6 months at time of screening.
  3. Nadir CD4 count less than 250 and current CD4 counts greater than 100 cells/ul.
  4. hs-CRP levels above 2mg/L.
  5. Willingness to use a method of contraception during the study period.
  6. Willingness to comply with study evaluations for LP sub-study.
  7. Karnofsky performance score of 80 or higher.
  8. If female, willing to undergo pregnancy testing on a monthly basis and not breastfeeding.

Exclusion Criteria:

  1. Concomitant use of fibric acid derivatives or other lipid lowering agents including patients on statins and Ezetimibe.
  2. Use of any anti-inflammatory drugs (OTC or prescription) on a daily basis.
  3. Pregnancy or breastfeeding
  4. Active drug use or alcohol abuse/dependence which in the opinion of researchers will interfere with the patients' ability to participate in the study.
  5. Allergy or hypersensitivity to Atorvastatin or any of its components.
  6. History of myositis or rhabdomyolysis with use of any statins.
  7. Patients who are on concurrent immunomodulatory agents, including systemic corticosteroids (nasal or inhaled) will be ineligible for 3 months after completion of therapy with the agent.
  8. History of inflammatory muscle disease such a poly or dermatomyositis.
  9. serious intercurrent illness requiring systemic treatment and/or hospitalization within 30 days of entry.
  10. Evidence of active opportunistic infections requiring treatment or neoplasms that require chemotherapy during study period.
  11. CPK greater than 3 times the ULN.
  12. Known active liver disease or AST/ALT greater than 3 times the ULN.
  13. Renal insufficiency, indicated by serum creatinine greater than 2mg/dL.
  14. Absolute neutrophil counts less than 1000/ul; hemoglobin less than 10g/dL for males and less than 9g/dL for females; platelet counts less than 100,000/mm3.
  15. Documented HCV infection.
  16. NYHA class III or IV congestive heart failure.
  17. Active IV drug use within 1 year prior to entry.
  18. For LP sub-study, allergy to Lidocaine.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01600170

Contacts
Contact: Joseph Quinn, RN 215-349-8091 joseph.quinn@uphs.upenn.edu
Contact: Yan Jiang, RN 215-349-8091 yanjiang19@gmail.com

Locations
United States, Pennsylvania
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
University of Pennsylvania
Investigators
Principal Investigator: Ronald G Collman, MD University of Pennsylvania
  More Information

No publications provided

Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT01600170     History of Changes
Other Study ID Numbers: IRB Protocol # 815512
Study First Received: May 14, 2012
Last Updated: May 25, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by University of Pennsylvania:
HIV
monocytes
CD16+
 statins
mcp1
inflammation

Additional relevant MeSH terms:
AIDS Dementia Complex
Dementia
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Immunologic Deficiency Syndromes
 Immune System Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Atorvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Enzyme Inhibitors
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on March 05, 2013